Side-chain crystallizable polymers for medical applications

ABSTRACT

Inherently radiopaque side-chain crystallizable polymers (IRSCCP&#39;s) are useful in various medical applications. An example of a IRSCCP is a polymer that comprises a main chain, a plurality of crystallizable side chains, and a plurality of heavy atoms attached to the polymer, the heavy atoms being present in an amount that is effective to render the polymer radiopaque. A polymeric material that includes a IRSCCP may be fabricated into a medical device useful for at least partially occluding a body cavity. For example, such a medical device may be an embolotherapy product.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/586,796, filed Jul. 8, 2004, which is hereby incorporated byreference in its entirety.

BACKGROUND

1. Field of the Invention

This invention relates to side-chain crystallizable polymers, andparticularly to inherently radiopaque side-chain crystallizable polymersuseful in medical applications.

2. Description of the Related Art

Polymeric materials are widely used in numerous applications. Forexample, therapeutic embolization is the selective blockage of bloodvessels or diseased vascular structures. Examples of polymericembolotherapy devices and reagents include embolic coils, gel foams,glues, and particulate polymeric embolic agents used, for example, tocontrol bleeding, prevent blood loss prior to or during a surgicalprocedure, restrict or block blood supply to tumors and vascularmalformations, e.g., for uterine fibroids, tumors (i.e.,chemo-embolization), hemorrhage (e.g., during trauma with bleeding) andarteriovenous malformations, fistulas (e.g., AVF's) and aneurysms.

Polymeric liquid embolic agents include precipitative and reactivesystems. For example, in a precipitative system, a polymer may bedissolved in a biologically acceptable solvent that dissipates uponvascular delivery, leaving the polymer to precipitate in situ. Reactivesystems include cyanoacrylate systems in which, e.g., a liquid monomericand/or oligomeric cyanoacrylate mixture is introduced to the vascularsite through a catheter and polymerized in situ. In this system,polymerization is initiated by the available water in the blood.

A number of technological applications involve the use of a polymer thatundergoes a transition upon a change in temperature. For example, in themedical field, one way to introduce a solid polymer into a particularbody region is to heat the polymer into a flowable state, then injectthe polymer into the region and allow it to cool and solidify. U.S. Pat.No. 5,469,867 discloses side-chain crystallizable polymers that are saidto be useful for occluding channels in a living mammal. Such polymersare said to be designed such that they can be melted so that they areflowable slightly above body temperature but solidify when cooled tobody temperature.

SUMMARY

An embodiment provides a polymer that includes a main chain, a pluralityof crystallizable side chains, and a plurality of heavy atoms attachedto the polymer, the heavy atoms being present in an amount that iseffective to render the polymer radiopaque. Another embodiment providesa medical device that comprises such a polymer.

Another embodiment provides a medical device that includes a polymericmaterial, the polymeric material comprising a biocompatible inherentlyradiopaque side chain crystallizable polymer.

Another embodiment provides a method of treatment that includesintroducing a medical device into a body cavity of a mammal in an amountthat is effective to at least partially occlude the body cavity, whereinthe medical device comprises a polymeric material, and wherein thepolymeric material comprises a biocompatible inherently radiopaque sidechain crystallizable polymer.

Another embodiment provides a method for making an inherently radiopaqueside chain crystallizable polymer, comprising copolymerizing a firstmonomer and a second monomer, the first monomer comprising a heavy atomand the second monomer comprising a crystallizable group.

Another embodiment provides a method for making an inherently radiopaqueside chain crystallizable polymer, comprising reacting a side chaincrystallizable polymer with a heavy metal reagent under conditionsselected to attach a plurality of heavy atoms to the side chaincrystallizable polymer.

These and other embodiments are described in greater detail below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment provides an inherently radiopaque side chaincrystallizable polymer (“IRSCCP”). IRSCCP's may be used in a variety ofapplications, including medical applications in which their inherentradiopacity may provide significant advantages. The term “inherentlyradiopaque polymer” is used herein to refer to a polymer to which heavyatoms are attached by covalent or ionic bonds to render the polymereasier to detect by medical imaging techniques (e.g., by X-rays and/orduring fluoroscopy). In this context, a “heavy atom” is an atom that,when attached to a polymer, renders the polymer easier to detect by animaging technique as compared to a polymer that does not contain theheavy atom. Since many polymers contain relatively low atomic numberatoms such as hydrogen, carbon, nitrogen, oxygen, silicon and sulfur, inmost cases heavy atoms have an atomic number of 17 or greater. Preferredheavy atoms have an atomic number of 35 or greater, and include bromine,iodine, bismuth, gold, platinum tantalum, tungsten, and barium.

IRSCCP's also contain crystallizable side chains. Side chaincrystallizable (SCC) polymers, sometimes called “comb-like” polymers,are well-known, see N. A. Plate and V. P. Shibaev, J. Polymer Sci.:Macromol. Rev. 8:117-253 (1974), the disclosure of which is herebyincorporated by reference. IRSCCP's may be SCC polymers that have beenmodified to include heavy atoms, e.g., by bonding heavy atoms to an SCCpolymer and/or by making an IRSCCP by polymerizing monomers that containheavy atoms. IRSCCP's may have various configurations, e.g.,homopolymer, copolymer (e.g., random copolymer, alternating copolymer,block copolymer, graft copolymer), various tacticities (e.g., random,isotactic, atactic, syndiotactic), etc. An IRSCCP may be a mixture orblend of two or more IRSCCP's, each of the individual IRSCCP's in themixture or blend having different configurations, molecular weights,melting points, etc. The polymer backbone or main chain of the IRSCCP,to which the crystallizable side chains are attached, may be configuredin various ways, e.g., linear, branched, crosslinked, dendritic,single-stranded, double-stranded, etc. Preferred IRSCCP's for medicalapplications are biocompatible and/or bioresorbable. The heavy atoms maybe attached to the main chain and/or the side chains of an IRSCCP.

The crystallizable side chains of IRSCCP's are preferably selected tocrystallize with one another to form crystalline regions and maycomprise, for example, —(CH₂)_(n)— and/or —((CH₂)_(m)—O—)_(n) groups.The side chains are preferably linear to facilitate crystallization. ForIRSCCP's that contain —(CH₂)_(n)— groups in the crystallizable sidechain, n is preferably in the range of about 6 to about 30, morepreferably in the range of about 20 to about 30. For IRSCCP's thatcontain —((CH₂)_(m)—O—)_(n) groups in the crystallizable side chain, nis preferably in the range of about 6 to about 30 and m is preferably inthe range of about 1 to about 8. More preferably, m and n are selectedso that the ((CH₂)_(m)—O—)_(n) groups contain from about 6 to about 30carbon atoms, even more preferably from about 20 to about 30 carbonatoms. The spacing between side chains and the length and type of sidechain are preferably selected to provide the resulting IRSCCP with adesired melting point. For example, for medical applications (e.g.,embolotherapy), the spacing between side chains and the length and typeof the side chains are preferably selected to provide the IRSCCP (and/orthe material into which it is incorporated) with a melting point in therange of about 30° C. to about 80° C. As the spacing between side chainsincreases, the tendency for the side chains to be crystallizable tendsto decrease. Likewise, as the flexibility of the side chains increases,the tendency for the side chains to be crystallizable tends to decrease.On the other hand, as the length of the side chains increases, thetendency for the side chains to be crystallizable tends to increase. Inmany cases, the length of the IRSCCP crystallizable side chain may be inthe range of about two times to about ten times the average distancebetween crystallizable side chains.

Examples of IRSCCP's include versions of the following polymers that aremodified to include sufficient heavy atoms to render them radiopaque andselected so that the alkyl group is sufficiently long (e.g., greaterthan about 6 carbons) to provide the desired melting point:poly(1-alkene)s, poly(alkyl acrylate)s, poly(alkyl methacrylate)s,poly(alkyl vinyl ether)s, and poly(alkyl styrene)s. Examples of IRSCCP'sfurther include versions of the polymers disclosed in the followingreferences that include (or have been modified to include)crystallizable side chains and sufficient heavy atoms to render themradiopaque: U.S. Pat. Nos. 4,638,045; 4,863,735; 5,198,507; 5,469,867;5,912,225; and 6,238,687; as well as U.S. Provisional Patent ApplicationNo. 60/601,526, filed 13 Aug. 2004; all of which are incorporated byreference in their entireties, and particularly for the purpose ofdescribing SCC polymers and methods for making them.

In an embodiment, the side chains are selected to provide the IRSCCP (ormaterial into which the IRSCCP is incorporated) with a controllablemelting temperature. In a preferred embodiment, polymeric embolotherapyproducts include IRSCCP's, thereby rendering the embolotherapy productdetectable by a technique such as X-ray. The side chains of the includedIRSCCP may be selected so that the polymeric embolotherapy product has amelting point higher than the body temperature of the mammal for whichthe product is intended. Such a polymeric embolotherapy product may, forexample, be heated above the melting temperature to render it moreflowable, thereby facilitating delivery to the target vasculature, whereit may cool and solidify to embolize the vasculature. The use ofIRSCCP's to provide radiopacity and a controlled melting point may beparticularly advantageous in medical applications, but those skilled inthe art will recognize additional applications as well. Thus, while thevarious descriptions herein regarding the use of IRSCCP's may indicate apreference for medical applications, it will be understood that varioustechnologies outside the medical area may also benefit from the use ofIRSCCP's.

Furthermore, in some embodiments, the present polymers may be used todevelop various medical devices. For instance, pre-fabricatedoff-the-shelf devices, rapidly prototyped devices, real-time prototypedevices using computer technology. Additionally present polymers may bedelivered directly to a non-lumen or non-cavity of the body. The variousmedical devices may include but are not limited to stents and stentgrafts for vascular and body lumen applications, pins, screws, sutures,anchors and plates for reconstructive skeletal or soft tissueapplications, cartilage replacements. IRSCCP may placed directly in bodytissue for example in subcutaneous and intramuscular tissue.

An embodiment of an IRSCCP is a polymer comprising a main chain, aplurality of crystallizable side chains, and a plurality of heavy atomsattached to the polymer, the heavy atoms being present in an amount thatis effective to render the polymer radiopaque. A polymer that comprisesa recurring unit of the formula (I) is an example of such an IRSCCP:

In formula (I), X¹ and X² are each independently selected from the groupconsisting of Br and I; y¹ and y² are each independently zero or aninteger in the range of 1 to 4; and A¹ is selected from the groupconsisting of

R³ is selected from the group consisting of C₁-C₃₀ alkyl, C₁-C₃₀heteroalkyl, C₅-C₃₀ aryl, C₆-C₃₀ alkylaryl, and C₂-C₃₀ heteroaryl; R⁴selected from the group consisting of H, C₁-C₃₀ alkyl, and C₁-C₃₀heteroalkyl; R¹ is

R⁵ and R⁶ are each independently selected from the group consisting of—CH═CH—, —CHJ¹—CHJ²—, and —(CH₂)_(a)—; a is zero or an integer in therange of 1 to 8; J¹ and J² are each independently selected from thegroup consisting of Br and I; and Z is an O or an S; and Q is acrystallizable group comprising from about 6 to about 30 carbon atoms,preferably from about 20 to about 30 carbon atoms. In an embodiment, Qis:

Polymers of the formula (I) may be prepared by modifying the generalmethods described in U.S. Provisional Patent Application No. 60/601,526,filed 13 Aug. 2004, to select the appropriate side chain length, sidechain spacing and halogen content.

It will be recognized that Q and/or R⁴ may comprise crystallizable sidechains, that each of X, J¹ and J² is a heavy atom, and that y may beadjusted so that the number of heavy atoms in the polymer is sufficientto render the polymer radiopaque. Q and R⁴ may each independentlycomprise units selected from the group consisting of —(CH₂)_(n1)— and—((CH₂)_(m1)—O—)_(n1); where m1 and n1 are each independently selectedso that Q and/or R⁴ each independently contain from about 1 to about 30carbon atoms, preferably from about 6 to about 30 carbon atoms, and morepreferably from about 20 to 30 carbon atoms. Moreover, Q and R⁴ mayinclude other functional groups such as ester and amide, and/or heavyatoms such as iodine and bromine. Non-limiting examples of Q and R⁴ thusinclude —C_(n1)H_(2nl+1), —CO₂—C_(n1)H_(2n+1), —CONH—C_(n1)H_(2n1+1),—(CH₂)_(n1)—Br, —(CH₂)_(n1)—I, —CO₂—(CH₂)_(n1)—Br, —CO₂—(CH₂)_(n1)—I,—CONH—CO₂—(CH₂)_(n1)—Br, and —CONH—CO₂—CH₂)_(n1)—I. In an embodiment, R⁵is —CH═CH— or —(CH₂)_(a)—; R⁶ is —(CH₂)_(a)—; and Q is an ester groupcomprising from about 10 to about 30 carbon atoms.

It will be understood that a polymer that comprises a recurring unit ofthe formula (I) may be a copolymer, e.g., a polymer of the formula (I)that further comprises recurring —R²-A²- units, where R² is selectedfrom the group consisting of —(CH₂)_(n2)— and —((CH₂)_(m2)—O—)_(n2);where m2 and n2 are each independently selected so that R² contains fromabout 1 to about 30 carbon atoms; and where A² is defined in the samemanner as A¹ above. Thus, an embodiment provides a polymer comprisingrecurring units of the formula (Ia):

In formula (Ia), X¹, X², y¹, y², R¹ and A¹ are defined as describedabove for formula (I); p and q may each be independently varied over abroad range to provide a polymer having the desired properties, e.g.,melting point, radiopacity, and viscosity, using routineexperimentation. In an embodiment, p and q are each independently aninteger in the range of 1 to about 10,000. It will be appreciated thatthe formula (I) units and —(R²-A²)— units in a polymer comprisingrecurring units of the formula (Ia) may be arranged in various ways,e.g., in the form of a block copolymer, random copolymer, alternatingcopolymer, etc.

Another embodiment of an IRSCCP (e.g., a polymer comprising a mainchain, a plurality of crystallizable side chains, and a plurality ofheavy atoms attached to the polymer, the heavy atoms being present in anamount that is effective to render the polymer radiopaque) comprises arecurring unit of the formula (II):

In formula (II), R⁷ is H or CH₃; A³ is a chemical group having amolecular weight of about 500 or less; and A³ bears at least one of theheavy atoms attached to the polymer. Non-limiting examples of A³ includemetal carboxylate (e.g., —CO₂Cs), metal sulfonate (e.g., —SO₄Ba),halogenated alkyl ester (e.g., —CO₂—(CH₂)_(b)—Br), halogenated alkylamide (e.g., —CONH—(CH₂)_(b)—Br), and halogenated aromatic (e.g.,—C₆H₄—I), where b is an integer in the range of about 1 to about 4. Inan embodiment, A³ comprises an aromatic group bearing at least onehalogen atom selected from the group consisting of bromine and iodine.In another embodiment, A³ comprises a chemical group of the formula—L₁—(CH₂)_(n3)—L₂—Ar¹, wherein L₁ and L₂ each independently represent anullity (i.e., are not present), ester, ether or amide group; n3 is zeroor an integer in the range of about 1 to about 30; and Ar¹ comprises ahalogenated aromatic group containing from about 2 to about 20 carbonatoms. IRSCCP's that comprise a recurring unit of the formula (II) maybe formed by polymerization of the corresponding monomers or bypost-reaction of appropriate polymeric precursors. IRSCCP's thatcomprise a recurring unit of the formula (II) may be copolymers thatinclude additional recurring units.

Side chain A³ groups in an IRSCCP comprising a recurring unit of theformula (II) may be crystallizable and/or the IRSCCP comprising arecurring unit of the formula (II) may further comprise a secondrecurring unit that comprises a crystallizable side chain. Examples ofsuitable second recurring units having crystallizable side chainsinclude the following: poly(1-alkene)s, poly(alkyl acrylate)s,poly(alkyl methacrylate)s, poly(alkyl vinyl ether)s, and poly(alkylstyrene)s. The alkyl groups of the foregoing exemplary second recurringunits preferably contain more than 6 carbon atoms, and more preferablycontain from about 6 to about 30 carbon atoms. For example, in anembodiment, the second recurring unit is of the formula (III):

In formula (III), R⁸ is H or CH₃; L³ is an ester or amide linkage; andR⁹ comprises a C₆ to C₃₀ hydrocarbon group. IRSCCP's comprising arecurring unit of the formula (II) and a second recurring unit (such asa recurring unit of the formula (III)) may be formed by copolymerizationof the corresponding monomers and/or by post reaction of appropriatepolymeric precursors.

Another embodiment of an IRSCCP (e.g., a polymer comprising a mainchain, a plurality of crystallizable side chains, and a plurality ofheavy atoms attached to the polymer, the heavy atoms being present in anamount that is effective to render the polymer radiopaque) comprises arecurring unit of the formula (IV), where A³ is defined above:

In formula (IV), A⁴ represents H or a group containing from about 1 toabout 30 carbons, e.g., a C₁-C₃₀ hydrocarbon. Side chain A³ and/or A⁴groups in an IRSCCP comprising a recurring unit of the formula (IV) maybe crystallizable and/or the IRSCCP comprising a recurring unit of theformula (IV) may further comprise a second recurring unit that comprisesa crystallizable side chain. For example, in an embodiment, the secondrecurring unit is of the formula (V), where R¹⁰ comprises a C₆ to C₃₀hydrocarbon group and R¹¹ represents H or a group containing from about1 to about 30 carbons, e.g., a C₁-C₃₀ hydrocarbon:

IRSCCP's are not limited to those comprising recurring units of theformulae (I) to (V), and further include versions of known polymers thathave been modified to include side-chain crystallizable groups and/orsufficient heavy atoms to render the resulting polymer radiopaque. Thoseskilled in the art will understand that IRSCCP's may be prepared invarious ways, e.g., by employing routine experimentation to modify knownmethods for making SCC polymers to thereby incorporate heavy atoms intothe resulting polymers. For example, inherently radiopaque versions ofthe side chain crystallizable polymers described in U.S. Pat. No.5,469,867 may be prepared by copolymerizing the corresponding monomerswith monomers that contain heavy atoms. U.S. Pat. No. 5,469,867 isincorporated by reference and particularly for the purpose of describingmonomers, polymers and methods of polymerization. Examples of suitablemonomers that contain heavy atoms are disclosed in Kruft, et al.,“Studies On Radio-opaque Polymeric Biomaterials With PotentialApplications To Endovascular Prostheses,” Biomaterials 17 (1996)1803-1812; and Jayakrishnan et al., “Synthesis and Polymerization ofSome Iodine-Containing Monomers for Biomedical Applications,” J. Appl.Polm. Sci., 44 (1992) 743-748. IRSCCP's may also be prepared bypost-reaction, e.g., by attaching heavy atoms to the polymers describedin U.S. Pat. No. 5,469,867. Specific examples of polymers that may bemodified with heavy atoms to make IRSCCP's include the acrylate,fluoroacrylate, methacrylate and vinyl ester polymers described in J.Poly. Sci, 10.3347 (1972); J. Poly. Sci. 10:1657 (1972); J. Poly. Sci.9:3367 (1971); J. Poly. Sci. 9:3349 (1971); J. Poly. Sci. 9:1835 (1971);J.A.C.S. 76:6280 (1954); J. Poly. Sci. 7:3053 (1969); Polymer J. 17:991(1985), corresponding acrylamides, substituted acrylamide and maleimidepolymers (J. Poly. Sci.: Poly. Physics Ed. 11:2197 (1980); polyolefinpolymers such as those described in J. Poly. Sci.: Macromol. Rev.8:117-253 (1974) and Macromolecules 13:12 (1980), polyalkyl vinylethers,polyalkylethylene oxides such as those described in Macromolecules 13:15(1980), alkylphosphazene polymers, polyamino acids such as thosedescribed in Poly. Sci. USSR 21:241, Macromolecules 18:2141,polyisocyanates such as those described in Macromolecules 12:94 (1979),polyurethanes made by reacting amine- or alcohol-containing monomerswith long-chain alkyl isocyanates, polyesters and polyethers,polysiloxanes and polysilanes such as those described in Macromolecules19:611 (1986), and p-alkylstyrene polymers such as those described inJ.A.C.S. 75:3326 (1953) and J. Poly. Sci. 60:19 (1962). The foregoingpolymers may be modified with heavy atoms to make IRSCCP's in variousways. For example, monomers bearing heavy atoms may be prepared byiodinating and/or brominating the monomers used to make the foregoingpolymers. Those heavy atom-bearing monomers may then be copolymerizedwith the unmodified monomers to prepare IRSCCP's. Those skilled in theart may identify conditions for making the heavy atom-bearing monomersand corresponding IRSCCP's by routine experimentation.

In another embodiment, an IRSCCP is prepared by reacting a side chaincrystallizable polymer with a heavy metal reagent under conditionsselected to attach a plurality of heavy atoms to the side chaincrystallizable polymer. For example, the side chain crystallizablepolymer may be exposed to a heavy metal reagent that comprises bromineand/or iodine. Examples of heavy metal reagents include bromine vapor,iodine vapor, bromine solution and iodine solution. The side chaincrystallizable polymer may be exposed to the heavy metal reagent by,e.g., exposing or intermixing the solid polymer with heavy metal reagentand/or by dissolving or dispersing the side chain crystallizable polymerin a solvent and intermixing with the heavy metal reagent. Other methodsmay also be used.

IRSCCP's may contain various amounts of heavy atoms and crystallizableside chains, depending on the properties desired for the polymer.Preferably, the content of crystallizable side chains is sufficient tosubstantially reduce or prevent main chain crystallization. In manycases, the amount of crystallizable side chain in the IRSCCP is in therange of about 20% to about 80% by weight, based on total polymerweight, and in some cases may be in the range of about 35% to about 65%,same basis. The length of the IRSCCP crystallizable side chain ispreferably in the range of about two times to about ten times theaverage distance between crystallizable side chains. IRSCCP's maycomprise a crystalline region (e.g., formed by crystallization of theside chains below the melting point of the polymer) and anon-crystalline region (e.g., a glassy or elastomeric region formed bythe non-crystallizable portions of the IRSCCP). In an embodiment, thenon-crystalline region has a glass transition temperature that is higherthan the body temperature of a mammal, e.g., higher than about 37° C.;in another embodiment, the non-crystalline region has a glass transitiontemperature that is lower than the body temperature of a mammal, e.g.,lower than about 37° C. The amount of heavy atoms in a particular IRSCCPmay be selected based on the degree of radiopacity desired. For example,for medical applications, a IRSCCP preferably contains from about 1% toabout 90% heavy atoms, more preferably about 20% to about 50% by heavyatoms, by weight based on total weight of IRSCCP. In some cases, theIRSCCP is incorporated into a polymeric material and/or formed into amedical device as described below. In such cases, the amount of heavyatoms in the IRSCCP may be adjusted to provide the resulting polymericmaterial and/or medical device with the desired degree of radiopacity.

The indiscriminate incorporation of heavy atoms into side chaincrystallizable polymers often disrupts or prevents otherwisecrystallizable side chains from crystallizing, particularly when thelevels of heavy atom incorporation are high, the side chains arerelatively short, the side chains are relatively flexible, and/or thedistance between side chains is relatively large. Preferably, the heavyatoms are attached to the IRSCCP in a manner that minimizes oreliminates disruption of side chain crystallinity. For example, in anembodiment, at least about 50%, preferably at least about 80%, of theheavy atoms are attached to the main chain of the IRSCCP. In anotherembodiment, at least about 50%, preferably at least about 80%, of theheavy atoms are attached to the ends of the side chains of the IRSCCP,e.g., to the ends of the crystallizable side chains and/or tonon-crystallizable side chains. In another embodiment, at least about50%, preferably at least about 80%, of the heavy atoms are attached toeither the main chain or the side chains (crystallizable and/ornon-crystallizable) of the IRSCCP. In another embodiment, the IRSCCP isa block copolymer that comprises a crystalline block and an amorphousblock, and at least about 50%, preferably at least about 80%, of theheavy atoms are attached to the amorphous block.

The molecular weight of IRSCCP's may be selected in view of the intendedapplication for the polymer. For example, in some medical applications,e.g., for certain embolotherapy applications, it is desirable for theIRSCCP to flow at temperatures higher than the polymer melting point andto form a solid at temperatures below the polymer melting point. Theviscosity of molten IRSCCP generally increases as the molecular weightof the polymer increases, and thus the molecular weight of a particularIRSCCP is preferably selected to provide the desired molten polymerviscosity. For example, a suitable molecular weight range for IRSCCP'sused in embolotherapy products may be in the range of from about 2,000to about 250,000, preferably from about 5,000 to about 150,000.Molecular weights are weight average as determined by high pressure sizeexclusion chromatography using light scattering detection.

In some cases, it may be desirable to mix or blend the IRSCCP with asecond material (e.g., a second polymer) to form a polymeric material,which may then be employed in the intended application. For example, anembodiment provides a polymeric material that comprises a IRSCCP and asecond polymer. Preferably, the second polymer is biocompatible and/orbioresorbable. Examples of second polymers suitable for mixing orblending with IRSCCP's to form polymeric materials include thenon-inherently radiopaque polymers disclosed in U.S. Pat. No. 5,469,867and the radiopaque polymers described in U.S. Provisional PatentApplication No. 60/601,526, filed 13 Aug. 2004, both of which areincorporated by reference. Depending on the intended application, therelative amounts of IRSCCP and second polymer in the polymeric materialmay vary over a broad range. For example, in an embodiment, a polymericmaterial comprises from about 1% to about 100% of a IRSCCP and up toabout 99% of a second polymer, by weight based on total. Since apolymeric material may consist solely of IRSCCP, it will be appreciatedthat the term “polymeric material” as used herein includes IRSCCP's. Asnoted above, it will be understood that the IRSCCP itself may be amixture or blend of two or more individual IRSCCP's, each having, forexample, different molecular weights, configurations and/or meltingpoints.

A polymeric material that comprises a IRSCCP may be formed into variousconfigurations or pre-formed shapes, e.g., a rod, a particle, or asheet. A rod may be linear, coiled, hollow, highly elongated (e.g., astring or strand), and may have various cross-sections shapes, e.g.,substantially round, substantially elliptical, substantially triangular,substantially rectangular, irregular, etc. A particle may be a sphericalparticle, a geometrically non-uniform particle (e.g., a flake or chip),a porous particle, a hollow particle, a solid particle, etc. A particlepreferably has a excluded diameter of from about 10 microns to about5,000 microns.

The configuration of the polymeric material may depend on variousfactors such as the intended application, shipping constraints,processing constraints, etc. For example, an embodiment provides amedical device that comprises a polymeric material. The polymericmaterial may comprise a IRSCCP. Various medical device embodiments aredescribed in greater detail below. It will be appreciated that a medicaldevice may consist solely of a polymeric material that consists solelyof a IRSCCP. For example, in an embodiment, a medical device isconfigured to be deliverable (e.g., by injection, catheter, physicalinsertion, pouring, spraying and/or squirting) to a body cavity of amammal. Such a device may be, for example, an embolotherapy productformed primarily of a polymeric material that comprises a IRSCCP. Thus,while certain descriptions below may be directed to medical devices, itwill be understood that such descriptions also apply to polymericmaterials and to IRSCCP's, unless the context indicates otherwise.Likewise, descriptions herein of polymeric materials and to IRSCCP'salso apply to medical devices, unless the context indicates otherwise.

A medical device that comprises a polymeric material may include one ormore additional components, e.g., a plasticizer, a filler, acrystallization nucleating agent, a preservative, a stabilizer, aphotoactivation agent, etc., depending on the intended application. Forexample, in an embodiment, a medical device comprises an effectiveamount of at least one therapeutic agent and/or a magnetic resonanceenhancing agent. Non-limiting examples of preferred therapeutic agentsinclude a chemotherapeutic agent, a non-steroidal anti-inflammatory, asteroidal anti-inflammatory, and a wound healing agent. Therapeuticagents may be co-administered with the polymeric material. In apreferred embodiment, at least a portion of the therapeutic agent iscontained within the polymeric material. In another embodiment, at leasta portion of the therapeutic agent is contained within a coating on thesurface of the medical device.

Non-limiting examples of preferred chemotherapeutic agents includetaxanes, taxinines, taxols, paclitaxel, dioxorubicin, cis-platin,adriamycin, and bleomycin. Non-limiting examples of preferrednon-steroidal anti-inflammatory compounds include aspirin,dexamethasone, ibuprofen, naproxen, and Cox-2 inhibitors (e.g.,Rofexcoxib, Celecoxib and Valdecoxib). Non-limiting examples ofpreferred steroidal anti-inflammatory compounds include dexamethasone,beclomethasone, hydrocortisone, and prednisone. Mixtures comprising oneor more therapeutic agents may be used. Non-limiting examples ofpreferred magnetic resonance enhancing agents include gadolinium saltssuch as gadolinium carbonate, gadolinium oxide, gadolinium chloride, andmixtures thereof.

Nucleating agents are materials that, in the presence of a polymer, makecrystallization of the polymer more thermodynamically favorable. Forexample, a nucleating agent may accelerate polymer crystallization at agiven temperature and/or induce crystallization (e.g., of a supercooledpolymer) at a higher temperature than in the absence of the nucleatingagent. Non-limiting examples of preferred nucleating agents include lowmolecular weight analogs of the IRSCCP's with higher peakcrystallization temperatures than the bulk polymer being crystallized,carboxylate salts (such as sodium benzoate), inorganic salts (such asbarium sulfate) and various particulate materials with relatively highsurface area to volume ratios.

The amounts of additional components present in the medical device arepreferably selected to be effective for the intended application. Forexample, a therapeutic agent is preferably present in the medical devicein an amount that is effective to achieve the desired therapeutic effectin the patient to whom the medical device is administered or implanted.Such amounts may be determined by routine experimentation. In certainembodiments, the desired therapeutic effect is a biological response. Inan embodiment, the therapeutic agent in the medical device is selectedto promote at least one biological response, preferably a biologicalresponse selected from the group consisting of thrombosis, cellattachment, cell proliferation, attraction of inflammatory cells,deposition of matrix proteins, inhibition of thrombosis, inhibition ofcell attachment, inhibition of cell proliferation, inhibition ofinflammatory cells, and inhibition of deposition of matrix proteins. Theamount of magnetic resonance enhancing agent in a medical devices ispreferably an amount that is effective to facilitate radiologic imaging,and may be determined by routine experimentation.

The viscosity and/or melting point of a medical device that comprises aIRSCCP typically depends on the relative amounts of the IRSCCP and othercomponents, if any, present in the medical device. The viscosity and/ormelting point of the medical device (or polymeric material in themedical device) may be controlled by manipulating the amount of IRSCCPin the medical device and by selecting a IRSCCP that provides theresulting medical device with the desired viscosity and/or meltingpoint. Thus, for example, to provide a polymeric material that has amelting point of 40° C., it may be desirable to select a IRSCCP that hasa somewhat higher melting point, e.g., about 45° C., for incorporationinto the polymeric material, to compensate for the presence of a secondpolymer or other component that has a tendency to lower the meltingpoint of the IRSCCP when in admixture with it. In an embodiment, amedical device comprises a polymeric material that has a melting pointin the range of about 30° C. to about 80° C.

The polymeric material of the medical device is preferably configured toflow at a temperature above the melting point. The viscosity of thepolymeric material at the temperature above the melting point may varyover a broad range, depending on factors such as the intendedapplication. For example, for embolotherapy products, the polymericmaterial preferably has a viscosity above the melting point that allowsthe medical device to be delivered to the target vasculature by aconvenient technique such as by injection through a syringe and/or byflowing through a catheter. In such cases, the desired viscosity oftendepends on the diameter of the syringe needle or catheter, e.g., lowerviscosities are typically preferred at smaller diameters. On the otherhand, if the viscosity is too low, the polymeric material may migrateaway from the target vasculature prior to cooling and solidifying. In anembodiment, the polymeric material of the medical device has a viscosityin the range of about 50 cP to about 500 cP at the temperature above themelting point. In another embodiment, the polymeric material has aviscosity in the range of about 500 cP to about 5,000 cP at thetemperature above the melting point. In another embodiment, thepolymeric material has a viscosity in the range of about 5,000 cP toabout 250,000 cP at the temperature above the melting point. In anotherembodiment, the polymeric material has a viscosity in the range of about250,000 cP to about 1,000,000 cP at the temperature above the meltingpoint.

In an embodiment, the polymeric material is configured to form a solidmass upon delivery to a body cavity. The solid mass may wholly orpartially conform to an interior dimension of the body cavity. Forexample, the polymeric material may be configured to contain an amountof an IRSCCP that provides the polymeric material with a melting pointof about 40° C. The polymeric material may be further configured to bedeliverable to the body cavity, e.g., the polymeric material may be inthe form of a rod that may be heated to a molten state to facilitateflow. The molten polymeric material may then be delivered to a bodycavity by flowing through a delivery device in the molten state. Uponarrival in the body cavity, the molten polymeric material may at leastpartially conform to the interior dimension of the body cavity, thencool to form a solid mass. As another example, the polymeric materialmay be in the form of small particles suspended in a relatively lowviscosity biocompatible carrier liquid such as water or saline. Thepolymeric material may then be caused to flow through a delivery deviceto the target body cavity. The small particle of polymeric material maybe heated prior to delivery, during delivery and/or within the targetcavity by, thereby causing the polymeric material to flow and conform toan interior dimension of the body cavity. Upon cooling, the polymericmaterial may form a solid mass that continues to conform to the interiordimension of the body cavity. It will be understood that polymericmaterials of various configurations and formulations before heating mayvary in their ability to conform to the body cavity once warmed and maytherefore be selected for this reason to tailor the treatment. Further,it will be understood that the polymeric material need not be completelymelted to achieve delivery. For example, a polymeric material may beformed into a particular shape, such as a coil, then implanted into thetarget body cavity while retaining the preformed shape. The polymericmaterial (e.g., coil) may be heated prior to and/or during implantationfor various reasons, e.g., to render the coil more resilient and thuseasier to deliver, and/or to enable the coil to better conform to thebody cavity into which it is implanted. The polymeric material may alsobe caused to flow outside the body then be delivered to the body cavityin a flowable state.

An embodiment provides a shape memory polymeric material that comprisesa IRSCCP. For example, a IRSCCP may be configured into a first shapesuch as a coiled shape by a standard thermoplastic formation process andcrosslinked to fix the memory of the first shape. The formed IRSCCP coilmay then be heated to melt the IRSCCP, allowing it to be re-configuredinto a second shape such as a rod shape. The cross-linking limits orprevents thermoplastic flow while the IRSCCP is in the melted state. TheIRSCCP while still in the second shape may then be cooled to atemperature at which the IRSCCP recrystallizes. The recrystallization ofthe IRSCCP limits or prevents the second shape (e.g., the rod shape)from returning to the first shape (e.g., the coil shape). Uponre-heating to a temperature above the melting point of the IRSCCP, thesecond shape returns to the first shape, e.g., the rod reverts to itsmemory state of a coil. Crosslinking of the IRSCCP may be carried out invarious ways known to those skilled in the art.

An embodiment provides a method of treatment that comprises introducinga medical device as described herein (e.g., a medical device thatcomprises an IRSCCP) into a body cavity of a mammal in an amount that iseffective to at least partially occlude the body cavity. In general,such a method may be used to occlude any type body cavity including,e.g., various body cavities that may commonly be referred to as tubes,tubules, ducts, channels, foramens, vessels, voids, and canals. In apreferred embodiment, the medical device is an embolotherapy product. Inanother preferred embodiment, the body cavity comprises vasculature,e.g., an arteriovenous malformation or a blood vessel such as a varicosevein. The medical device may be introduced to the body cavity in avariety of ways, including by injection, by catheter and by surgicalimplantation. For a particular body cavity, the medical device ispreferably selected so that the polymeric material has a melting pointthat is sufficiently high that the polymer forms a solid mass at thenormal temperature of the body cavity, and sufficiently low so that thatsoftened or molten polymeric material may conform to a dimension of thebody cavity with little or no thermal damage to the mammal into which itis introduced. Introduction of such a polymeric material into the bodycavity thus may comprise heating the polymeric material to a temperaturethat is higher than the melting point and/or cooling it to a temperaturethat is lower than the melting point.

Various types of delivery devices may be used to introduce the medicaldevice to the body cavity, e.g., plastic tubes, catheters, fine cannula,tapered cannula and various types of syringes and hypodermic needleswhich are generally known to and available to those in the medicalprofession. An embodiment provides a medical apparatus that comprises apolymeric material and a delivery device, where the polymeric materialis an IRSCCP, and where the polymeric material and the delivery deviceare mutually configured to facilitate delivery of the polymeric materialto a body cavity by the delivery device. The polymeric material ispreferably contained within the delivery device, in an amount that mayvary somewhat depending on the particular body cavity to be occluded andthe amount and type of occlusion desired. Those skilled in the art willbe aware of the size of the cavity being occluded based on the size ofthe patient, general knowledge of anatomy, and thus use of diagnosticmethods such as X-ray and MRI. Those skilled in the art will be able todetermine the amount of polymer material to be included within thedelivery device. In general, an excess amount of polymeric materialshould be included in the delivery device in order to provide for acertain margin of error. In an embodiment, the medical apparatuscomprises an embolotherapy product and a tube, where the embolotherapyproduct comprises a IRSCCP as described herein and where the tube isconfigured to facilitate flow of the embolotherapy product to a bodycavity. For example, the tube may comprise a needle, cannula, syringe,and/or catheter, and may be equipped with a heater configured to heatthe embolotherapy product to a temperature above its melting point,e.g., to a temperature in the range of about 30° C. to about 80° C. Thepolymeric material may be included within the delivery device in a solidform or heated separately and provided in the delivery device in aflowable form. In one embodiment, the medical apparatus may beprepackaged with the polymeric material present within the deliverydevice and may thereafter be heated in order to make the polymericmaterial flowable. Heating may be applied from an exterior source suchas an air, water or oil bath or an electrical heater, in which case boththe delivery device and the polymeric material may be heated. Heatingcan also be applied from an interior source, e.g., using a smallelectrical resistive element at the end of a catheter through which athin rod of the solid polymeric material is passed, or using a smalllaser directed at the tip of a rod of polymeric material emerging fromthe end of a catheter.

The delivery device may include an extrusion nozzle which is preferablyrelatively small in diameter such that it will not seriously damage thetissue in the vicinity of the body cavity to be occluded, butsufficiently large such that the polymeric material can be readilyextruded from the nozzle. For example, in application that involves theocclusion of a body channel, the size of the nozzle is generally relatedto the inside diameter of the channel into which it is placed. Forexample, a 24 gauge needle typically fits within the opening of thepunctum which leads to the canaliculus. A 2 mm catheter is typicallyappropriate for introducing the polymeric material into the fallopiantubes. A ¼ inch cannula is preferred for introducing the polymericmaterial into the inner cavity of an adult humerus. When delivered inthe molten state, the polymeric material is preferably selected to havea viscosity that facilitates passage of the polymeric material throughthe extrusion nozzle. In general, relatively lower viscosities arepreferred for relatively smaller diameter nozzles.

It will be understood that the delivery device may include an extrusionnozzle with one or more delivery ports. The polymeric material may bedispensed through multiple ports serially or simultaneously. Thisapproach may accommodate better packing and/or stabilization of thepolymeric material that cools and it may allow for delivery of morepolymeric material across a large surface area. That variousconfigurations and formulations may be simultaneously delivered by theuse of various delivery ports.

For example, in an embodiment, two or more polymeric materials (eachcomprising a IRSCCP) may be delivered sequentially to a body cavity. Inan embolotherapy embodiment, a first polymeric material is delivered tovascular structure. The first polymeric material may have a firstconfiguration, such as a coil. The coil may be preformed, e.g., a shapememory coil as described above that is delivered in a rod shape (forminga coil upon delivery), or may be a coil that is formed during deliveryby extruding the polymeric material through a delivery port of thedelivery device having an appropriately configured die. The firstpolymeric material is preferably delivered at a temperature higher thanits melting point, e.g., higher than the melting point of a first IRSCCPin the first polymeric material.

A coil may be a relatively open structure that partially occludes thevascular structure, reducing the blood flow without completely stoppingit. Although such partial occlusion may be appropriate in some cases, inother cases further occlusion may be desired. Such further occlusion maybe accomplished by delivering a second polymeric to the vascularstructure in operable proximity to the first polymeric material. Thesecond polymeric material is preferably delivered at a temperaturehigher than the its melting point, e.g., higher than the melting pointof a second IRSCCP in the second polymeric material. The secondpolymeric material preferably has a lower viscosity than the firstpolymeric material, such that it may at least partially fill intersticesor gaps in the first polymeric material and/or between the firstpolymeric material and the interior of the vascular structure. Thus, forexample, the second polymeric material may have the consistency of apaste at a temperature above its melting point during delivery, allowingit to fill in the spaces of the first polymeric material coil.

One or more additional polymeric materials may be delivered to alocation in operable proximity to the first and second polymericmaterials. For example, the first and second polymeric materials mayonly partially occlude the vascular structure, although typically to agreater extend than the first polymer alone. In such a case, it may bedesirable to deliver a third polymeric material to provide furtherocclusion. The third polymeric material is preferably delivered at atemperature higher than the its melting point, e.g., higher than themelting point of a third IRSCCP in the third polymeric material. Thethird polymeric material preferably has a lower viscosity than the firstpolymeric material, and more preferably lower than the second polymericmaterial, such that it may at least partially fill interstices or gapsin the polymeric mass formed by the first and second polymeric materialsand/or between the mass and the interior of the vascular structure.

Those skilled in the art will appreciate that multiple variations of theembodiments described above may be practiced. For example, a singlepolymeric material may be delivered in multiple doses or in differentforms, e.g., as a coil in a first delivery and as a paste in a seconddelivery, or as a paste in both the first and second deliveries. Two ormore polymeric materials may be delivered simultaneously, e.g., a firstpolymeric material in a coil shape may be coated or mixed with a secondpolymeric material in a paste or liquid form to form a composite thatcomprises both polymers, and the resulting composite may then bedelivered to the body cavity. Various body cavities may be the target ofthe delivery, and/or the order in which the various polymeric materialsand forms are delivered may be varied. Delivery of a polymeric materialthat comprises a IRSCCP may be combined, sequentially or simultaneously,with the delivery of a different material, e.g., a metal embolic coil.Thus, for example, a polymeric material may be delivered to a bodycavity, and a metal embolic coil may be delivered to the body cavity incontact with the polymeric material. Various periods of time may passbetween deliveries, e.g., a polymeric material coil may be delivered toprovide partial occlusion of a body cavity, and a second polymericmaterial paste may be delivered to a location in operable proximity tothe coil minutes, hours, days, weeks, months, or years later.

For embodiments in which the polymeric material is delivered in themolten state, once a polymeric material has been included within thedelivery device and heated to a flowable state, the nozzle of thedelivery device (e.g., such as the tip of a needle, catheter, and/orsquirt nozzle) may be inserted into an opening of a channel (or throughthe wall of cavity) to be occluded and the polymer may be dispensed outof the nozzle into the body cavity. The injection is preferablycontinued until the desired amount of occlusion (e.g., vasculatureblockage) is obtained. In some instances, it may be desirable to occludeonly part of a cavity. Thereafter, the nozzle of the delivery device maybe withdrawn.

After the polymeric material has been delivered, the method may continuewithout operator interaction. For example, in the case of embolotherapy,the circulatory system of the mammal will typically cause a coolingeffect on the surrounding tissues which will cool the injected polymericmaterial. The polymeric material is preferably selected such that itcools and solidifies after losing only a small amount of energy, i.e.,hardens after decreasing in temperature by only a few degreescentigrade. Usually, cooling takes only a few seconds or minutes tooccur, although there are times when it may be desirable for cooling tooccur more slowly, e.g., in the case where a bone is reset afterdelivery. After cooling has taken place, the polymer preferablysolidifies within the cavity in a manner conforming to the shape of thecavity and the channel is at least partially filled or blocked. Thepolymeric material may remain in place in the cavity over long periodsof time. For preferred medical devices comprising biocompatible,non-immunogenic material, little or no adverse reaction is obtained. Incertain embodiment, the polymer is bioresorbable, and thus may diminishover time, in which case surrounding tissue may fill the previouslyoccluded region.

An effective cavity occlusion may also be achieved through the use ofIRSCCP material and various excipients. For instance, the IRSCCPmaterial may be delivered with (1) a photopolymerizable material thatcross links through the use of a light; (2) a blood reactive substancethat stimulates clotting such as collagen or thrombin, and/or (3) anucleating agent.

In an embodiment, the polymeric material may be readily removed so as toagain provide a cavity which functions in a normal manner. For example,it may be desirable to remove the polymeric material from a vas deferensor fallopian tube to restore fertility. The polymeric material may beremoved in various ways. For example, the polymeric material may beremoved by simple mechanical extraction. In certain instances, devicessuch as forceps and/or catheters with various attachment prongsconnected thereto can be inserted into the channel and used to attach tothe polymeric material and pull the polymeric material out of the cavityor force it forward into a second cavity so that the first cavity is nolonger occluded and the polymeric material will not cause any damage.Alternatively, a device such as a heated wire may be brought intocontact with the solidified polymeric material. By heating the polymericmaterial with the heated wire, the temperature of the polymeric materialis raised above the melting point of the polymeric material so that itagain becomes flowable. In the case of a channel (such as a duct orvein), the heating may be continued until the flowable polymericmaterial flows from the channel and the channel is reopened to providenormal function. In certain circumstances, the liquid plug can be drawn,aspirated or forced out of a channel, e.g., by suction with a gentlevacuum or by using mild pressure created by air or a saline flow and/orby mechanical breakup along with trapping and aspiration.

A preferred method of removing the solidified polymeric material from achannel or other cavity is to inject a lipophilic material such as anaturally occurring oil or a fatty acid ester into the channel in thearea surrounding the solidified polymeric material. Preferably, alipophilic material is selected that has a tendency to diffuse into thepolymeric material, thereby reducing its melting point. The lipophilicmaterial is preferably added in an amount that is effective to reducethe melting point of the polymeric material below body temperature tosuch an extent that the polymer becomes flowable. Once the polymerbecomes flowable, the natural mechanical movement that occurs withinchannels of living beings will tend to move the polymer from thechannel, thereby restoring the normal function of the channel.

EXAMPLE 1

To a resin flask equipped with a thermometer, stirrer and refluxcondenser is added 500 grams (g) of octamethylcyclotetrasiloxane, 250 gof octaphenylcyclotetrasiloxane, and 250 g ofocta(iodophenyl)cyclotetrasiloxane, a heavy atom-bearing monomer. Theflask and contents are heated to 150° C. and 0.11 g of potassiumhydroxide-isopropanol complex (neutral equivalent=193.5) is added (Si:Kratio about 4470:1). The solution is allowed to stir for approximately30 minutes. Once the solution becomes too viscous to stir effectively(due to polymer formation), the polymer is heated to approximately 165°C. for 3 to 4 hours, then cooled to room temperature. The resultingpolymer is a IRSCCP comprising recurring units of the formula (IV) inwhich A³ and A⁴ are iodinated phenyl groups, recurring units of theformula (V) in which R¹⁰ and R¹¹ are phenyl groups, and dimethylsiloxanerecurring units.

EXAMPLE 2

To a resin flask equipped with a thermometer, stirrer, reflux condenserand 250 g of xylene stirred at approximately 135° C., a solution of 20 gof 4-iodo styrene, 60 g of docosanyl acrylate, and 11 g of di-tert-butylperoxide is added over a period of approximately 3 hours. After additionis complete, the mixture is allowed to continue stirring forapproximately another 3 hours to affect a more complete conversion, thencooled to room temperature. The resulting polymer is a IRSCCP comprisingrecurring units of the formula (II) in which R⁷ and R⁸ are H, A³ isC₆H₄—I, and recurring units of the formula (III) in which L³ is an esterlinkage and R⁹ comprises a C₂₋₂ hydrocarbon group.

EXAMPLE 3

To a 500 mL 2-necked round-bottom flask equipped with a mechanicalstirrer and a rubber septum, 30 g of a monomer of the formula (VI)(12DT-docosanyl) and 240 ml of methylene chloride are added. The solidsare dissolved with stirring. About 4.34 g of triphosgene dissolved in 30mL of methylene chloride is placed in a airtight syringe and added tothe reaction flask with a syringe pump at a constant rate over a periodof about 2 to 3 hours. The resulting viscous polymer solution is dilutedby adding about 150 mL of tetrahydrofuran and 10 mL of water. Thepolymer is isolated by precipitating the polymer solution inisopropanol, filtering the resulting solid and drying under vacuum. Thepolymer is a IRSCCP comprising a recurring unit of the formula (I) inwhich X¹ is I, y¹ is 2, y² is zero, A¹ is —(C═O)—, R⁵ is —CH₂CH₂—, R⁶ is—CH₂—, and Q is a crystallizable ester group containing 23 carbons.

EXAMPLE 4

An embolization is carried out as follows: A IRSCCP prepared asdescribed in Example 3 is formed into a rod-shaped embolic medicaldevice and loaded into a heated catheter. A physician delivers thecatheter to a Arteriovenous Fistula (AVF) to be embolized. A baselineangiogram is performed with fluoroscopy to better determine the regionto be embolized. The rod of IRSCCP embolic agent is pushed through thecatheter to the target site. Localized heating in the catheter melts theIRSCCP, allowing it to flow through the catheter and to the target sitein an liquid form that conforms to the AVF and embolizes the tissue. TheIRSCCP cools and recrystallizes at the target site. Delivery of theIRSCCP is continued until blood flow ceases in the target area. Bloodflow cessation is confirmed by injecting contrast agent and viewing byfluoroscopy. The IRSCCP is visible under fluoroscopy. The catheter iscooled to stop the flow of unneeded IRSCCP. The catheter is withdrawn.

EXAMPLE 5

An embolization is carried out as described in Example 4, except that ahigher viscosity IRSCCP is utilized and the IRSCCP is delivered to anartery for the treatment of an aneurysm. Embolization is achieved.

EXAMPLE 6

Embolization of a traumatic bleeding artery is carried out as generallydescribed in Example 4, except that, prior to delivery, the IRSCCP isformed into the shape of a coil and crosslinked by irradiation, therebyforming a memory coil. During heating, the memory coil softens and formsa flexible rod that is delivered to the artery through the catheter.Upon delivery, the flexible rod cools and resumes a coil shape withinthe artery, thereby reducing the blood flow.

It will be appreciated by those skilled in the art that variousomissions, additions and modifications may be made to the materials andmethods described above without departing from the scope of theinvention, and all such modifications and changes are intended to fallwithin the scope of the invention, as defined by the appended claims.

1. A polymer comprising: a main chain; a plurality of crystallizableside chains; and a plurality of heavy atoms attached to the polymer, theheavy atoms being present in an amount that is effective to render thepolymer radiopaque.
 2. The polymer of claim 1 having a melting point inthe range of about 30° C. to about 80° C.
 3. The polymer of claim 1 thatis biocompatible.
 4. The polymer of claim 1 that is bioresorbable. 5.The polymer of claim 1 in which the plurality of heavy atoms comprise anatom having an atomic number of at least
 17. 6. The polymer of claim 5in which the plurality of heavy atoms comprise an atom having an atomicnumber of at least
 35. 7. The polymer of claim 1 in which the pluralityof heavy atoms comprise an atom selected from the group consisting ofbromine, iodine, bismuth, gold, platinum tantalum, tungsten, and barium.8. The polymer of claim 1 in which the plurality of heavy atoms arecovalently attached to the polymer.
 9. The polymer of claim 1 in whichthe plurality of heavy atoms are ionically attached to the polymer. 10.The polymer of claim 1 that is a copolymer comprising at least twodifferent recurring units.
 11. The polymer of claim 10 that is a randomcopolymer.
 12. The polymer of claim 10 that is a block copolymer. 13.The polymer of claim 1 in which the heavy atoms are attached to thepolymer in a manner that minimizes disruption of side chaincrystallinity.
 14. The polymer of claim 1 that comprises a recurringunit of the formula (I):

wherein: X¹ and X² are each independently selected from the groupconsisting of Br and I; y¹ and y² are each independently zero or aninteger in the range of 1 to 4; A¹ is selected from the group consistingof

R³ is selected from the group consisting of C₁-C₃₀ alkyl, C₁-C₃₀heteroalkyl, C₅-C₃₀ aryl, C₆-C₃₀ alkylaryl, and C₂-C₃₀ heteroaryl; R⁴selected from the group consisting of H, C₁-C₃₀ alkyl, and C₁-C₃₀heteroalkyl; R¹ is

Z is O or S; R⁵ and R⁶ are each independently selected from the groupconsisting of —CH═CH—, —CHJ¹—CHJ²—, and —(CH₂)_(a)—; a is zero or aninteger in the range of 1 to 8; J¹ and J² are each independentlyselected from the group consisting of Br and I; and Q is acrystallizable group comprising from about 6 to about 30 carbon atoms.15. The polymer of claim 14 in which Q comprises from about 20 to about30 carbon atoms.
 16. The polymer of claim 14 in which R⁵ is —CH═CH— or—(CH₂)_(a)—; R⁶ is —(CH₂)_(a)—; and Q is an ester group comprising fromabout 10 to about 30 carbon atoms.
 17. The polymer of claim 1 thatcomprises a recurring unit of the formula (II):

wherein R⁷ is H or CH₃; A³ is a chemical group having a molecular weightof about 500 or less; and A³ bears at least one of the heavy atomsattached to the polymer.
 18. The polymer of claim 17 in which A³comprises a metal carboxylate or metal sulfonate.
 19. The polymer ofclaim 18 in which A³ comprises barium.
 20. The polymer of claim 17 inwhich A³ comprises an ester or amide linkage.
 21. The polymer of claim17 in which A³ comprises an aromatic group bearing at least one halogenatom selected from the group consisting of bromine and iodine.
 22. Thepolymer of claim 17 in which A³ comprises a chemical group of theformula —L₁—(CH₂)_(n2)-L₂—Ar¹, wherein L₁ and L₂ each independentlyrepresent a nullity, ester, ether or amide group; n2 is zero or aninteger in the range of about 1 to about 30; and Ar¹ comprises ahalogenated aromatic group containing from about 2 to about 20 carbonatoms.
 23. The polymer of claim 17 that comprises a second recurringunit, the second recurring unit comprising at least one of thecrystallizable side chains.
 24. The polymer of claim 23 in which thesecond recurring unit is of the formula (III):

wherein R⁸ is H or CH₃; L³ is an ester or amide linkage; and R⁹comprises a C₆ to C₃₀ hydrocarbon group.
 25. The polymer of claim 1 thatcomprises a recurring unit of the formula (IV):

wherein A⁴ represents H or a chemical group containing from about 1 toabout 30 carbons; A³ is a chemical group having a molecular weight ofabout 500 or less; and A³ bears at least one of the heavy atoms attachedto the polymer.
 26. The polymer of claim 25 in which A³ comprises anaromatic group bearing at least one halogen atom selected from the groupconsisting of bromine and iodine.
 27. The polymer of claim 25 thatcomprises a second recurring unit, the second recurring unit comprisingat least one of the crystallizable side chains.
 28. The polymer of claim27 in which the second recurring unit is of the formula (V):

wherein R comprises a C₆ to C₃₀ hydrocarbon group and R¹¹ represents Hor a C₁ to C₃₀ hydrocarbon group.
 29. A medical device that comprisesthe polymer of claim
 1. 30. The medical device of claim 29 that furthercomprises an effective amount of at least one therapeutic agent.
 31. Amedical device that comprises a polymeric material, the polymericmaterial comprising a biocompatible inherently radiopaque side chaincrystallizable polymer.
 32. The medical device of claim 31 in which thepolymeric material comprises a second polymer in admixture with theinherently radiopaque polymer.
 33. The medical device of claim 31 inwhich the inherently radiopaque polymer is bioresorbable.
 34. Themedical device of claim 31 that is configured to be deliverable to abody cavity of a mammal.
 35. The medical device of claim 34 that isconfigured to be deliverable by injection or by catheter.
 36. Themedical device of claim 34 that comprises an embolotherapy product, theembolotherapy product comprising at least a portion of the inherentlyradiopaque polymer.
 37. The medical device of claim 36 in which at leasta portion of the inherently radiopaque polymer in the embolotherapyproduct is formed into at least one configuration selected from thegroup consisting of a rod, a particle, or a sheet.
 38. The medicaldevice of claim 37 in which the rod is in the form of a coil.
 39. Themedical device of claim 38 in which the coil is a memory coil.
 40. Themedical device of claim 37 in which the particle is selected from thegroup consisting of a spherical particle, a geometrically non-uniformparticle, a porous particle, a hollow particle, a solid particle, and aparticle having an excluded diameter of from about 10 microns to about5,000 microns.
 41. The medical device of claim 40 in which thegeometrically non-uniform particle is a flake or a chip.
 42. The medicaldevice of claim 34 in which the polymeric material has a melting pointin the range of about 30° C. to about 80° C.
 43. The medical device ofclaim 42 in which the polymeric material is configured to flow at atemperature above the melting point.
 44. The medical device of claim 43in which the polymeric material has a viscosity in the range of about 50cP to about 500 cP at the temperature above the melting point.
 45. Themedical device of claim 43 in which the polymeric material has aviscosity in the range of about 500 cP to about 5,000 cP at thetemperature above the melting point.
 46. The medical device of claim 43in which the polymeric material has a viscosity in the range of about5,000 cP to about 250,000 cP at the temperature above the melting point.47. The medical device of claim 43 in which the polymeric material has aviscosity in the range of about 250,000 cP to about 1,000,000 cP at thetemperature above the melting point.
 48. The medical device of claim 43in which the polymeric material comprises a crystalline region and anon-crystalline region at a temperature below the body temperature ofthe mammal.
 49. The medical device of claim 48 in which thenon-crystalline region has a glass transition temperature that is higherthan the body temperature.
 50. The medical device of claim 48 in whichthe non-crystalline region has a glass transition temperature that islower than the body temperature.
 51. The medical device of claim 43 inwhich the polymeric material is configured to form a solid mass upondelivery to the body cavity, the solid mass at least particallyconforming to an interior dimension of the body cavity.
 52. The medicaldevice of claim 51 in which the polymeric material comprises anexcipient selected from the group consisting of a photopolymerizablematerial, a blood reactive substance and a nucleating agent.
 53. Themedical device of claim 51 in which the solid mass retains a preformedshape.
 54. The medical device of claim 53 in which the preformed shapeis a coil.
 55. The medical device of claim 31 that further comprises aneffective amount of at least one therapeutic agent.
 56. The medicaldevice of claim 55 in which the therapeutic agent is selected from thegroup consisting of a chemotherapeutic agent, a non-steroidalanti-inflammatory, a steroidal anti-inflammatory, and a wound healingagent.
 57. The medical device of claim 55 in which the therapeutic agentis selected to promote at least one biological response.
 58. The medicaldevice of claim 57 in which the biological response is selected from thegroup consisting of thrombosis, cell attachment, cell proliferation,attraction of inflammatory cells, deposition of matrix proteins,inhibition of thrombosis, inhibition of cell attachment, inhibition ofcell proliferation, inhibition of inflammatory cells, and inhibition ofdeposition of matrix proteins.
 59. The medical device of claim 55 inwhich at least a portion of the therapeutic agent is contained withinthe polymeric material.
 60. The medical device of claim 59 in which atleast a portion of the therapeutic agent is releasable from thepolymeric material upon heating.
 61. The medical device of claim 31 thatfurther comprises an effective amount of at least one magnetic resonanceenhancing agent.
 62. A method of treatment comprising introducing amedical device into a body cavity of a mammal in an amount that iseffective to at least partially occlude the body cavity, wherein themedical device comprises a polymeric material, and wherein the polymericmaterial comprises a biocompatible inherently radiopaque side chaincrystallizable polymer.
 63. The method of claim 62 in which the bodycavity is selected from the group consisting of a tube, a tubule, aduct, a channel, a foramen, a vessel, a void, and a canal.
 64. Themethod of claim 62 in which the polymeric material has a melting pointin the range of about 30° C. to about 80° C.
 65. The method of claim 64in which introducing the medical device into the body cavity comprisesheating the polymeric material to a temperature that is higher than themelting point.
 66. The method of claim 65 in which introducing themedical device into the body cavity comprises cooling the polymericmaterial to a temperature that is lower than the melting point.
 67. Themethod of claim 66 in which the body cavity is a blood vessel.
 68. Themethod of claim 67 in which the blood vessel is a varicose vein.
 69. Themethod of claim 67 in which introducing the medical device into theblood vessel comprises flowing the polymeric material through acatheter, a syringe, a nozzle or combination thereof.
 70. A method formaking an inherently radiopaque side chain crystallizable polymer,comprising copolymerizing a first monomer and a second monomer, thefirst monomer comprising a heavy atom and the second monomer comprisinga crystallizable group.
 71. The method of claim 70 in which the heavyatom is selected from the group consisting of bromine and iodine. 72.The method of claim 70 in which the crystallizable group comprises fromabout 6 to about 30 carbon atoms.
 73. A method for making an inherentlyradiopaque side chain crystallizable polymer, comprising reacting a sidechain crystallizable polymer with a heavy metal reagent under conditionsselected to attach a plurality of heavy atoms to the side chaincrystallizable polymer.
 74. The method of claim 73 in which the heavymetal reagent comprises bromine.
 75. The method of claim 73 in which theheavy metal reagent comprises iodine.